CN103923039A - Method for preparing dianhydrogalactitol - Google Patents
Method for preparing dianhydrogalactitol Download PDFInfo
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- CN103923039A CN103923039A CN201410044162.5A CN201410044162A CN103923039A CN 103923039 A CN103923039 A CN 103923039A CN 201410044162 A CN201410044162 A CN 201410044162A CN 103923039 A CN103923039 A CN 103923039A
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- Prior art keywords
- dianhydrogalactitol
- add
- mitolactol
- galactitol
- crystallization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/24—Synthesis of the oxirane ring by splitting off HAL—Y from compounds containing the radical HAL—C—C—OY
- C07D301/26—Y being hydrogen
Abstract
The invention discloses a method for preparing dianhydrogalactitol. The method comprises the following steps: diluting by a xylose mother liquor, carrying out decoloring filtration, carrying out ion exchange, and carrying out chromatographic separation to obtain a xylose and glucose mixed liquor and a galactose and arabinose mixed liquor; carrying out evaporative concentration on the galactose and arabinose mixed liquor, carrying out catalytic hydrogenation, carrying out decoloring filtration, carrying out ion exchange, and evaporating to supersaturation in order to obtain crystallized dulcitol; and reacting dulcitol with hydrobromic acid to prepare 1,6-bromodulcitol; and dissolving 1,6-bromodulcitol in t-butyl alcohol of potash, and carrying out an elimination reaction to prepare dianhydrogalactitol. The xylose mother liquor can be prepared by hydrolyzing one or more of corncobs, bagasse, sugarcane pith, cottonseed hulls and rice hulls. Highly pure dianhydrogalactitol can be produced through the method.
Description
[technical field]
The present invention relates to a kind of preparation method, specifically relate to a kind of method of preparing dianhydrogalactitol.
[background technology]
Xylitol, has another name called pentitol, is a kind of five-carbon sugar alcohol, and molecular formula is C
5h
12o
5, be the intermediate product of xylose metabolism, be extensively present in the plants such as the group food of fruit, vegetables, cereal, mushroom and timber, straw, corn cob.Be widely used in food service industry as sweeting agent Xylitol, and as clinical nutrition agent and the therapeutical agent of diabetes and hepatitis.It or important industrial chemicals in addition, is widely used in the aspects such as leather, plastics and coating.Galactitol, has another name called sweet and pure, melampyrum, hexan-hexol, and molecular formula is C
6h
14o
6.At occurring in nature, it is mainly present in the certain plants of Wei Mao section plant and mountain trailing plants Pittosporum, because its content is very low, and usually mixes with other material, so the production of galactitol is very difficult with preparation, market value is very high.Galactitol is microorganisms, the requisite important carbohydrate of preventing and curing diseases, and its injection liquid is also the rheumatoid medicine for the treatment of.Dianhydrogalactitol, has another name called dianhydrogalactitol, dianhydrogalactitol, and DAG, dianhydrogalactitol, molecular formula is C
6h
10o
4, be the converted product of 1,6-mitolactol, there is the effect of retardance cell proliferation, be novel plant alkaloid series antineoplastic medicament.At present domestic freeze-dried powder dianhydrogalactitol system is taking the Maytenus confertflora J. Y. Luo et X X Chen. extract of Guangxi special product as the synthetic dianhydrogalactitol of raw material, and its source is limited, expensive.
Chinese patent 201010129819.X has introduced a kind of technique of simultaneously producing Xylitol and galactitol.The galactitol purity of producing lower.Chinese patent 201180050124.6 has been introduced a kind of effective ways of synthetic and two dewatering hexitols (for example dianhydrogalactitol) of purifying.Adopting Maytenus confertflora J. Y. Luo et X X Chen. is that raw material is prepared galactitol, then prepares dianhydrogalactitol with the galactitol of producing.This method raw material sources are narrow, and preparation cost is higher.
[summary of the invention]
For addressing the above problem, the invention provides a kind of new method of preparing dianhydrogalactitol, make xylose mother liquid after decolouring, accelerate filtration velocity, reduce production cost, produce highly purified dianhydrogalactitol.
For achieving the above object, the present invention is by the following technical solutions:
Prepare a method for dianhydrogalactitol, its step comprises:
(1) under stirring with the speed of 150r/min～180r/min, in the xylose mother liquid that is 32～38% in mass percent concentration, add gac and silicon-dioxide, be heated to 60～68 DEG C, insulation 31～60min decolours, filtration, filtrate are carried out the laggard row chromatographic separation of ion-exchange through cation and anion exchange post; Described chromatographic separation is the simulation moving-bed separation with 8 posts at 55 DEG C～65 DEG C, and separating agent is chlorine type basic anion chromatographic separation resin, and eluent is to be 7.0～7.5, Cl through the pH of cation and anion exchange post processing
-≤ 15ppm, the deionized water of specific conductivity≤20 μ S/cm, wash-out obtains the mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose; Wherein, the mixed liquid concentration of xylose and glucose is 15～25%, and wherein Xylose Content is 75～90%, and glucose content is 5～20%; The mixed liquid concentration of semi-lactosi and pectinose is 5～10%, and wherein galactose content is 45～65%, and pectinose content is 25～35%;
(2) mass percent concentration of semi-lactosi step (1) being obtained through chromatographic separation and pectinose mixed solution evaporation concentration to 38～43%, shortening obtains the mixed solution of galactitol and arabitol;
(3) to step (2) mixed solution decolouring, filtration, ion-exchange, be evaporated to after supersaturation, add galactitol crystal seed and growth stimulant, crystallization obtains crystallization galactitol;
(4) at 70 DEG C～80 DEG C, the galactitol that step (3) is obtained reacts 7～8 hours with the Hydrogen bromide of mass percentage concentration≤70%, pours product in frozen water crystallization, and anhydrous tertiary butanol washing is dry, obtains the crystallization of 1,6-mitolactol;
(5) step (4) is made 1,6-mitolactol is dissolved in the trimethyl carbinol, adds mitolactol crystal seed, is cooled to-15 DEG C～0 DEG C under stirring, leave standstill 5～10 days, obtain 1,6-mitolactol product, wash with anhydrous tertiary butanol, dry, obtain 1,6-mitolactol;
(6) product step (5) being made is dissolved in the trimethyl carbinol that contains salt of wormwood, at 80 DEG C～82 DEG C, reflux 1～3 hour, make dianhydrogalactitol, gained dianhydrogalactitol is dissolved in the trimethyl carbinol, add dianhydrogalactitol crystal seed, be cooled to-15 DEG C～0 DEG C, leave standstill 1～5 day, with anhydrous tertiary butanol washing, dry, obtain dianhydrogalactitol crystallization, lyophilize obtains dianhydrogalactitol lyophilized powder.
Described silicon-dioxide is 5～10 object particles, and its addition is 0.2～1.5% of xylose mother liquid dry biomass, and the addition of described gac is 5～8% of xylose mother liquid dry biomass.Selecting silicon-dioxide instead of calcium oxide, is because calcium oxide can react with water, become thick obstruction and filter, and product is slightly soluble in water, can increase the impurity in solution, and silicon-dioxide stable performance, the impurity in can fast filtering solution.Silicon-dioxide addition is 0.6～1.2% of xylose mother liquid dry biomass, and the addition of described gac is 5～8% of xylose mother liquid dry biomass.
In described step (2), the condition of shortening is: material liquid pH is 7.5～8.0, adds radium niobium nickel catalyzator by 3～4% of dry biomass, and temperature of reaction is 125～135 DEG C, and pressure is 10～11MPa, and stirring velocity is 250～350r/min.
Galactitol crystal seed in described step (3) is solid galactitol, and add-on is 1.5%～2.5% of feed liquid quality; Described growth stimulant is potassium acetate and dehydrated alcohol, and its add-on is respectively as 2.5%～4.5% of 0.015%～0.9% and material liquid volume of feed liquid quality.
The process of crystallization comprises in described step (3): under stirring, be cooled to-15 DEG C～0 DEG C, leave standstill 5～10 days, and centrifugal, can obtain the galactitol crystal of 98% above purity; Hot ethanol dissolving for gained crystal, cooling recrystallization, absolute ethanol washing and dry, obtain crystallization galactitol, more than the purity to 99.8% of this galactitol.
The mitolactol kind crystalline substance adding in described step (5) is 1,6-mitolactol, described 1, in 6-mitolactol, contain 1,3-mitolactol massfraction is lower than 1%, and the brilliant add-on of described mitolactol kind is 1%～2% of feed liquid quality.
The dianhydrogalactitol kind crystalline substance adding in described step (6) is 1,2,5,6-dianhydrogalactitol, described 1,2,5, in 6-dianhydrogalactitol, contain 1,2,4,5-dianhydrogalactitol is lower than 1%, and the brilliant add-on of described dianhydrogalactitol kind is 1%～2% of feed liquid quality
The amount that adds salt of wormwood in described step (6) in the trimethyl carbinol is to add the ratio of 10～20g salt of wormwood to add in every hundred milliliters of trimethyl carbinols.
Preferably, the addition of described silica dioxide granule is 0.6～1.0% of xylose mother liquid dry biomass, and the addition of described gac is 5.5～7.5% of xylose mother liquid dry biomass.
Described in step (1), preparation method's step of xylose mother liquid comprises the steps:
A, by one or more raw materials of selecting from corn cob, bagasse, Pith, cotton seed hulls and rice husk, be crushed to 1～2mm, add deionized water, be heated to 80～100 DEG C, insulated and stirred 2～5 hours;
The hydrochloric acid that adds 3～5 times of mass concentrations 3～5% of solid volume after b, filtration in solid, under room temperature, the ultrasonication that is 100MHz through frequency 1～2 hour, is warming up to 100 DEG C of hydrolysis, refluxes 1～2 hour, and suction filtration obtains hydrolyzed solution;
C, said hydrolyzed liquid is heated to 75～80 DEG C, adding while stirring proportion is 0.9～1.05 calcium carbonate milk sap, in pH6～7.5 time, is incubated 1～2 hour, filter cleaner;
D, evaporation: reduction vaporization is concentrated into desired concn, obtain xylose mother liquid.
Preferably, in described step (4), hydrobromic mass percentage concentration is 65～70%, minimum must not be lower than 45%.Described Hydrogen bromide is for well with the hydrogen bromide solution of 65～70% concentration.
Another is preferred, and the ratio that the middle mitolactol of described step (5) is dissolved in the trimethyl carbinol is that 1g mitolactol is dissolved in the 10mL trimethyl carbinol.
With immediate prior art ratio, the excellent effect of method provided by the invention is:
1, owing to add gac in decolorization in, add silica dioxide granule, added the filtration velocity of calcium oxide to be greatly improved than adding gac in prior art simultaneously, guaranteed again good decolorizing effect simultaneously;
2, because the crystal growth promoters adding in the present invention is potassium acetate and dehydrated alcohol, reduced production cost;
3, compared with producing with prior art processes, the purity of dianhydrogalactitol of the present invention has improved, and its dianhydrogalactitol obtaining assorted peak in infrared colour spectrogram obviously reduces;
4, in production technique of the present invention taking xylose mother liquid as raw material, replaced Maytenus confertflora J. Y. Luo et X X Chen. extract, expanded the raw material sources of product;
5, its antitumor curative effect of dianhydrogalactitol that the present invention makes purity is higher is more obvious, can clinical application.
[embodiment]
Embodiment 1
Corn cob is cleaned and is crushed to 1mm, add deionized water in the ratio of material-water ratio 1:3, be heated to 100 DEG C, insulated and stirred 2 hours; After filtration, in solid, add 5 times of volumes of corn cob, the hydrochloric acid of mass concentration 5%, under room temperature, frequency 100MHz ultrasonication 1.5 hours, is warming up to 100 DEG C of hydrolysis, refluxes 2 hours, and suction filtration obtains hydrolyzed solution.In hydrolyzed solution, still contain HCl, therefore need neutralization.Said hydrolyzed liquid is heated to 78 DEG C, and adding while stirring proportion is 0.9 calcium carbonate milk sap, regulate and control to pH be 7, for making precipitation fully, insulation 1 hour after neutralization, filter cleaner.By the liquid glucose reduction vaporization after slagging-off, gained feed liquid is xylose mother liquid.In this feed liquid, contain semi-lactosi after testing.
Get mass concentration and be 65% xylose mother liquid, adding de-ionate, to be diluted to mass concentration be 32%, squeeze into decolouring still, add gac by 5% of dry biomass in xylose mother liquid, add 5 object silica dioxide granules simultaneously by 0.6% of dry biomass, tune mixing speed is 180r/min, feed temperature rises to after 68 DEG C, insulation 45min, filters, and obtains xylose mother liquid destainer; Wherein, described deionization is the deionized water of processing through cation and anion exchange post, and its pH is 7.0～7.5, Cl
-≤ 15ppm, specific conductivity≤20 μ S/cm.Destainer is carried out to ion-exchange through cation and anion exchange post, be purified liquid, in scavenging solution, Xylose Content is 59.52%, and glucose content is 8.69%, and galactose content is 18.78%, and pectinose content is 12.73%.Scavenging solution is squeezed into head tank, and controlling chromatographic fractionation system temperature is 55 DEG C, and the simulation moving-bed equipment of chlorine type basic anion chromatographic separation resin is housed through 8 posts, controls separation system pH7.0, Cl
-≤ 15ppm, the deionized water wash-out of specific conductivity≤20 μ S/cm, obtains the mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose.Wherein xylose and glucose mixed liquid concentration is 18.6%, and Xylose Content is 85.4%, and glucose content is 12.6%; Semi-lactosi and pectinose mixed liquid concentration are 7.5%, and galactose content is 56.6%, and pectinose content is 30.5%.
The mixed solution evaporation concentration of the semi-lactosi that chromatographic separation is obtained and pectinose to mass percentage concentration is 38%, flavouring liquid pH is 7.5, add radium niobium nickel catalyzator by 3% of dry biomass, temperature of reaction is 125 DEG C, and pressure is 10MPa, and stirring velocity is 250r/min, shortening, make the semi-lactosi in mixed solution change into galactitol, pectinose changes into arabitol, obtains the mixed solution of galactitol and arabitol.Mixed solution decolouring, filtration, ion-exchange, crystallization kettle are evaporated to supersaturation, add crystal galactitol by 2% of feed liquid quality, add potassium acetate and add dehydrated alcohol by 4% of material liquid volume by 0.02% of feed liquid quality simultaneously, under stirring, be cooled to 0 DEG C, leave standstill 5 days, centrifugal, obtain galactitol crystallization.By hot ethanol dissolving for this crystallization, cooling recrystallization, absolute ethanol washing and dry, obtain galactitol.The purity 99.8% of this galactitol.
The Hydrogen bromide that is 65% by the galactitol 9g of purity 99.8% and 18ml mass percentage concentration is at 80 DEG C, reflux 8 hours, make 1, 6-mitolactol, then product is poured into crystallization in frozen water, through anhydrous tertiary butanol washing, be dried and obtain 1, the crystallization of 6-mitolactol, then by 10.0g1, the crystallization of 6-mitolactol is dissolved in the trimethyl carbinol, add feed liquid quality 1% obtain through refining step containing 1, 3-mitolactol lower than 1% 1, 6-mitolactol crystal seed, stir, be cooled to 0 DEG C, leave standstill 10 days, obtain 1, the crystallization of 6-mitolactol, wash with anhydrous tertiary butanol, dry, obtain 1, 6-mitolactol.5g is made 1, 6-mitolactol is dissolved in the 50ml trimethyl carbinol that contains 8g salt of wormwood, eliminate reaction, at 81 DEG C, return time is 1 hour, products therefrom is dissolved in the trimethyl carbinol, add feed liquid quality 1% obtain through refining step containing 1, 2, 4, 5-dianhydrogalactitol lower than 1% 1, 2, 5, 6-dianhydrogalactitol kind is brilliant to be stirred, be cooled to 0 DEG C, leave standstill 5 days, obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, through anhydrous tertiary butanol washing, be dried and obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, lyophilize obtains dianhydrogalactitol lyophilized powder, containing 1, 2, 4, 5-dianhydrogalactitol is lower than 0.3%.
Under room temperature condition 1,2,5, the methanol solution of 6-dianhydrogalactitol, in 24 hours, does not find that rearrangement changes into 1,2, the phenomenon of 4,5-dianhydrogalactitol, when temperature is elevated to more than 37 DEG C 1, there is intramolecular rearrangement at solution state in 2,5,6-dianhydrogalactitol, change into 1,2,4, the phenomenon of 5-dianhydrogalactitol starts to occur, and becomes more and more obvious along with temperature raises.Solvent is changed into after the trimethyl carbinol, and it is not obvious that at same temperature, intramolecular rearrangement changes into the phenomenon of 1,2,4,5-dianhydrogalactitol.We notice that 1,2,5,6-dianhydrogalactitol exists intramolecular rearrangement to change into the fact of 1,2,4,5-dianhydrogalactitol at solution state, uses it for the refining step containing 1,2,4,5-dianhydrogalactitol sample.
Embodiment 2
Bagasse is cleaned and is crushed to 2mm, and by material-water ratio, 1:3 adds deionized water, is heated to 100 DEG C, insulated and stirred 3 hours; After filtration, in solid, add 5 times of solid volumes, the hydrochloric acid of mass concentration 5%, under room temperature, frequency 100MHz ultrasonication 2 hours, is warming up to 100 DEG C of hydrolysis, refluxes 1 hour, and suction filtration obtains hydrolyzed solution.Said hydrolyzed liquid is heated to 80 DEG C, and adding while stirring proportion is 1.05 calcium carbonate milk sap, regulate and control to pH be 6.5, for making precipitation fully, insulation 1 hour after neutralization, filter cleaner.By the liquid glucose reduction vaporization after slagging-off, gained feed liquid is xylose mother liquid.In this feed liquid, contain semi-lactosi after testing.
Get mass concentration and be 65% xylose mother liquid, adding de-ionate, to be diluted to mass concentration be 34%, squeeze into decolouring still, add gac by 8% of dry biomass in xylose mother liquid, add 10 object silica dioxide granules simultaneously by 1.5% of dry biomass, tune mixing speed is 150r/min, feed temperature rises to after 65 DEG C, insulation 35min, filters, and obtains xylose mother liquid destainer; Destainer is carried out to ion-exchange through cation and anion exchange post, be purified liquid, in scavenging solution, Xylose Content is 59.52%, and glucose content is 8.69%, and galactose content is 18.78%, and pectinose content is 12.73%.Scavenging solution is squeezed into head tank, and controlling separation system temperature is 55 DEG C, and the simulation moving-bed equipment of chlorine type basic anion chromatographic separation resin is housed through 8 posts, controls chromatographic fractionation system pH7.5, Cl
-≤ 15ppm, the deionized water wash-out of specific conductivity≤20 μ S/cm, obtains the mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose.Wherein xylose and glucose mixed liquid concentration is 16.4%, and Xylose Content is 79.8%, and glucose content is 11.8%; Semi-lactosi and pectinose mixed liquid concentration are 8.5%, and galactose content is 57.2%, and pectinose content is 25.5%.
The mixed solution evaporation concentration of the semi-lactosi that chromatographic separation is obtained and pectinose to mass percentage concentration is 40%, flavouring liquid pH is 7.8, add radium niobium nickel catalyzator by 4% of dry biomass, temperature of reaction is 130 DEG C, and pressure is 11MPa, and stirring velocity is 300r/min, shortening, make the semi-lactosi in mixed solution change into galactitol, pectinose changes into arabitol, obtains the mixed solution of galactitol and arabitol.Mixed solution decolouring, filtration, ion-exchange, crystallization kettle are evaporated to supersaturation, add crystal galactitol by 2.5% of feed liquid quality, add potassium acetate and add dehydrated alcohol by 3% of material liquid volume by 0.1% of feed liquid quality simultaneously, under stirring, be cooled to-5 DEG C, leave standstill 8 days, centrifugal, obtain galactitol crystallization.By hot ethanol dissolving for this crystallization, cooling recrystallization, absolute ethanol washing and dry, obtain galactitol.
The Hydrogen bromide that is 70% by the galactitol 10g of gained and 18ml mass percentage concentration is at 80 DEG C, reflux 7 hours, make 1,6-mitolactol, then product is poured into crystallization in frozen water, through anhydrous tertiary butanol washing, be dried and obtain the crystallization of 1,6-mitolactol, then by 1g1,6-mitolactol sample is dissolved in the trimethyl carbinol, adds through 1 of refining step acquisition, and 6-mitolactol crystal seed stirs, be cooled to 0 DEG C, leave standstill 10 days, obtain the crystallization of 1,6-mitolactol, wash with anhydrous tertiary butanol, dry, obtain 1,6-mitolactol.5g is made 1, 6-mitolactol is dissolved in the 50ml trimethyl carbinol that contains 10g salt of wormwood, eliminate reaction, at 80 DEG C, return time is 3 hours, products therefrom is dissolved in the trimethyl carbinol, what add the 1.5% process refining step acquisition of feed liquid quality contains 1, 2, 4, 5-dianhydrogalactitol lower than 1% 1, 2, 5, 6-dianhydrogalactitol kind is brilliant to be stirred, be cooled to 0 DEG C, leave standstill 5 days, obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, through anhydrous tertiary butanol washing, be dried and obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, lyophilize obtains dianhydrogalactitol lyophilized powder, containing 1, 2, 4, 5-dianhydrogalactitol is lower than 0.3%.
Embodiment 3
Corn cob and bagasse are cleaned and are crushed to 1mm, and by material-water ratio, 1:3 adds deionized water, is heated to 80 DEG C, insulated and stirred 4 hours; After draining, add 5 times of solid volumes, the hydrochloric acid of mass concentration 3%, under room temperature, frequency 100MHz ultrasonication 1.5 hours, is warming up to 100 DEG C of hydrolysis, refluxes 1.5 hours, and suction filtration obtains hydrolyzed solution.Said hydrolyzed liquid is heated to 78 DEG C, and adding while stirring proportion is 0.9 calcium carbonate milk sap, regulate and control to pH be 7, for making precipitation fully, insulation 1.5h after neutralization, filter cleaner.By the liquid glucose reduction vaporization after slagging-off, gained feed liquid is xylose mother liquid.In this feed liquid, contain semi-lactosi after testing.
Get mass concentration and be 65% xylose mother liquid, adding de-ionate, to be diluted to mass concentration be 38%, squeeze into decolouring still, add gac by 5.5% of dry biomass in xylose mother liquid, add 10 object silica dioxide granules simultaneously by 0.2% of dry biomass, tune mixing speed is 180r/min, feed temperature rises to after 62 DEG C, insulation 60min, filters, and obtains xylose mother liquid destainer; Destainer is carried out to ion-exchange through cation and anion exchange post, be purified liquid, in scavenging solution, Xylose Content is 59.52%, and glucose content is 8.69%, and galactose content is 18.78%, and pectinose content is 12.73%.Scavenging solution is squeezed into head tank, and controlling chromatographic fractionation system temperature is 55 DEG C, and the simulation moving-bed equipment of chlorine type basic anion chromatographic separation resin is housed through 8 posts, controls separation system pH7.2, Cl
-≤ 15ppm, the deionized water wash-out of specific conductivity 420 μ S/cm, obtains the mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose.Wherein xylose and glucose mixed liquid concentration is 20.4%, and Xylose Content is 75.4%, and glucose content is 17.6%; Semi-lactosi and pectinose mixed liquid concentration are 8%, and galactose content is 50.3%, and pectinose content is 28.9%.
The mixed solution evaporation concentration of the semi-lactosi that chromatographic separation is obtained and pectinose to mass percentage concentration is 43%, flavouring liquid pH is 8.0, add radium niobium nickel catalyzator by 3% of dry biomass, temperature of reaction is 135 DEG C, and pressure is 11MPa, and stirring velocity is 350r/min, shortening, make the semi-lactosi in mixed solution change into galactitol, pectinose changes into arabitol, obtains the mixed solution of galactitol and arabitol.Mixed solution decolouring, filtration, ion-exchange, crystallization kettle are evaporated to supersaturation, add crystal galactitol by 2% of feed liquid quality, add potassium acetate and add dehydrated alcohol by 4% of material liquid volume by 0.9% of feed liquid quality simultaneously, under stirring, be cooled to 0 DEG C, leave standstill 5 days, centrifugal, obtain galactitol crystallization.By hot ethanol dissolving for this crystallization, cooling recrystallization, absolute ethanol washing and dry, obtain galactitol.The purity 99.8% of this galactitol.
The Hydrogen bromide that is 69% by the galactitol 10g of purity 99.8% and 18ml mass percentage concentration is at 78 DEG C, reflux 8 hours, make 1, 6-mitolactol, then product is poured into crystallization in frozen water, through anhydrous tertiary butanol washing, be dried and obtain 1, the crystallization of 6-mitolactol, then by 1.0g1, 6-mitolactol sample is dissolved in the trimethyl carbinol, add feed liquid quality 1% through 1 of refining step acquisition, 6-mitolactol crystal seed stirs, be cooled to 0 DEG C, leave standstill 7 days, obtain 1, the crystallization of 6-mitolactol, wash with anhydrous tertiary butanol, dry, obtain 1, 6-mitolactol.5g is made 1, 6-mitolactol is dissolved in the 50ml trimethyl carbinol that contains 5g salt of wormwood, eliminate reaction, at 80 DEG C, return time is 2 hours, products therefrom is dissolved in the trimethyl carbinol, what add the 1% process refining step acquisition of feed liquid quality contains 1, 2, 4, 5-dianhydrogalactitol lower than 1% 1, 2, 5, 6-dianhydrogalactitol kind is brilliant to be stirred, be cooled to 0 DEG C, leave standstill 5 days, obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, through anhydrous tertiary butanol washing, be dried and obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, lyophilize obtains dianhydrogalactitol lyophilized powder, containing 1, 2, 4, 5-dianhydrogalactitol is lower than 0.3%.
Embodiment 4
Corn cob, bagasse, cotton seed hulls and rice husk are cleaned and are crushed to 1mm, and by material-water ratio, 1:3 adds deionized water, is heated to 90 DEG C, insulated and stirred 5 hours; After filtration, in solid, add 5 times of solid volumes, the hydrochloric acid of mass concentration 4%, under room temperature, frequency 100MHz ultrasonication 1 hour, is warming up to 100 DEG C of hydrolysis, refluxes 2 hours, and suction filtration obtains hydrolyzed solution.Said hydrolyzed liquid is heated to 78 DEG C, and adding while stirring proportion is 1.02 calcium carbonate milk sap, regulate and control to pH be 7.5, for making precipitation fully, insulation 2 hours after neutralization, filter cleaner.By the liquid glucose reduction vaporization after slagging-off, gained feed liquid is xylose mother liquid.In this feed liquid, contain semi-lactosi after testing.
Get mass concentration and be 65% xylose mother liquid, adding de-ionate, to be diluted to mass concentration be 36%, squeeze into decolouring still, add gac by 7.5% of dry biomass in xylose mother liquid, add 5 object silica dioxide granules simultaneously by 1% of dry biomass, tune mixing speed is 180r/min, feed temperature rises to after 68 DEG C, insulation 45min, filters, and obtains xylose mother liquid destainer; Destainer is carried out to ion-exchange through cation and anion exchange post, be purified liquid, in scavenging solution, Xylose Content is 59.52%, and glucose content is 8.69%, and galactose content is 18.78%, and pectinose content is 12.73%.Scavenging solution is squeezed into head tank, and controlling chromatographic fractionation system temperature is 55 DEG C, and the simulation moving-bed equipment of chlorine type basic anion chromatographic separation resin is housed through 8 posts, controls separation system pH7.2, Cl
-≤ 15ppm, the deionized water wash-out of specific conductivity≤20 μ S/cmm, obtains the mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose.Wherein xylose and glucose mixed liquid concentration is 23.1%, and Xylose Content is 78.8%, and glucose content is 10.6%; Semi-lactosi and pectinose mixed liquid concentration are 8.5%, and galactose content is 53.8%, and pectinose content is 26.5%.
The mixed solution evaporation concentration of the semi-lactosi that chromatographic separation is obtained and pectinose to mass percentage concentration is 43%, flavouring liquid pH is 8.0, add radium niobium nickel catalyzator by 3% of dry biomass, temperature of reaction is 135 DEG C, and pressure is 11MPa, and stirring velocity is 350r/min, shortening, make the semi-lactosi in mixed solution change into galactitol, pectinose changes into arabitol, obtains the mixed solution of galactitol and arabitol.Mixed solution decolouring, filtration, ion-exchange, crystallization kettle are evaporated to supersaturation, add crystal galactitol by 1.8% of feed liquid weight, add potassium acetate and add dehydrated alcohol by 2.5% of material liquid volume by 0.5% of feed liquid quality simultaneously, under stirring, be cooled to 0 DEG C, leave standstill 5 days, centrifugal, obtain galactitol crystallization.By hot ethanol dissolving for this crystallization, cooling recrystallization, absolute ethanol washing and dry, obtain galactitol.
The Hydrogen bromide that is 65% by the galactitol 9g of gained and 18ml mass percentage concentration is at 78 DEG C, reflux 8 hours, make 1, 6-mitolactol, then product is poured into crystallization in frozen water, through anhydrous tertiary butanol washing, be dried and obtain 1, the crystallization of 6-mitolactol, then by 10.0g1, 6-mitolactol sample is dissolved in the trimethyl carbinol, add feed liquid quality 2% through refining step obtain 1, 6-mitolactol crystal seed stirs, be cooled to 0 DEG C, leave standstill 7 days, obtain 1, the crystallization of 6-mitolactol, wash with anhydrous tertiary butanol, dry, obtain 1, 6-mitolactol.5g is made 1, 6-mitolactol is dissolved in the 50ml trimethyl carbinol that contains 5g salt of wormwood, eliminate reaction, at 80 DEG C, return time is 2 hours, products therefrom is dissolved in the trimethyl carbinol, add feed liquid quality 1% obtain through refining step containing 1, 2, 4, 5-dianhydrogalactitol lower than 1% 1, 2, 5, 6-dianhydrogalactitol kind is brilliant to be stirred, be cooled to 0 DEG C, leave standstill 1 day, obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, through anhydrous tertiary butanol washing, be dried and obtain 1, 2, 5, the crystallization of 6-dianhydrogalactitol, lyophilize obtains dianhydrogalactitol lyophilized powder, containing 1, 2, 4, 5-dianhydrogalactitol is lower than 0.3%.
The Structural Identification of dianhydrogalactitol:
The color atlas impurity peaks that the dianhydrogalactitol of preparing taking xylose mother liquid as raw material contains is less than Maytenus confertflora J. Y. Luo et X X Chen. extract taking Guangxi special product as the synthetic dianhydrogalactitol color atlas of raw material.
The galactitol extracting taking xylose mother liquid is done to inhibition test as the synthetic dianhydrogalactitol of raw material.Set up respectively human body glioma brain tumour (SHG-44) (Kunming mouse), adenocarcinoma of lung tumour (LAX) (Kunming mouse) mouse subcutaneous transplanting knurl model, experiment divides 2 groups, every group 6, male and female half and half, positive drug group abdominal injection dianhydrogalactitol, sample of the present invention is established 3 dosage groups, it is lotus knurl control group, dianhydrogalactitol low dose group (20mg/kg), middle dosage group (60mg/kg), high dose group (120mg/kg).Inoculated tumour started administration after 24 hours, each dosage group equal every day of intravenous administration, continuous 7 days.Within after last administration 24 hours, put to death animal, cut open and get knurl and heavily weigh, taking inhibition rate of tumor growth as evaluation index.
Test-results shows that human tumor heteroplastic transplantation model human body glioma brain tumour SHG-44 (subcutaneous vaccination) is had to obvious antitumor curative effect.Test-results is as follows:
The antitumor action of table 1 dianhydrogalactitol to human body glioma brain tumour (SHG-44) mouse
Test-results shows that Human Lung gland cancer tumour heteroplastic transplantation model LAX is had to obvious antitumor curative effect.Test-results is as follows:
The antitumor action of table 2 dianhydrogalactitol to adenocarcinoma of lung tumour (LAX) mouse
Therefore extract the synthetic dianhydrogalactitol of galactitol taking xylose mother liquid as raw material and there is pharmacology purposes, there is the advantage of clinical application.
Below be only the detailed description that preferred embodiment of the present invention is carried out, but the present invention is not limited to above embodiment.It should be understood that the various amendments that those skilled in the art makes, still belong to scope of the present invention in the spirit and scope situation of claim that does not depart from the application.
Claims (10)
1. a method of preparing dianhydrogalactitol, is characterized in that:
(1) under stirring with the speed of 150r/min～180r/min, in the xylose mother liquid that is 32～38% in mass percent concentration, add gac and silicon-dioxide, be heated to 60～68 DEG C, insulation 31～60min decolours, filtration, filtrate are carried out the laggard row chromatographic separation of ion-exchange through cation and anion exchange post; Described chromatographic separation is the simulation moving-bed separation with 8 posts at 55 DEG C～65 DEG C, and separating agent is chlorine type basic anion chromatographic separation resin, and eluent is to be 7.0～7.5, Cl through the pH of cation and anion exchange post processing
-≤ 15ppm, the deionized water of specific conductivity≤20 μ S/cm, the de-mixed solution of xylose and glucose and the mixed solution of semi-lactosi and pectinose of obtaining in Shen;
(2) step (1) is obtained through chromatographic separation, the semi-lactosi of the mass percent concentration of evaporation concentration to 38～43% and pectinose mixed solution, shortening obtains the mixed solution of galactitol and arabitol;
(3) to step (2) mixed solution decolouring, filtration, ion-exchange, be evaporated to after supersaturation, add galactitol crystal seed and growth stimulant, crystallization obtains crystallization galactitol;
(4) at 70 DEG C～80 DEG C, the galactitol that step (3) is obtained reacts 7～8 hours with the Hydrogen bromide of mass percentage concentration≤70%, pours product in frozen water crystallization, and anhydrous tertiary butanol washing is dry, obtains the crystallization of 1,6-mitolactol;
(5) step (4) is made 1,6-mitolactol is dissolved in the trimethyl carbinol, adds mitolactol crystal seed, is cooled to-15 DEG C～0 DEG C under stirring, leave standstill 5～10 days, obtain 1,6-mitolactol product, wash with anhydrous tertiary butanol, dry, obtain 1,6-mitolactol;
(6) product step (5) being made is dissolved in the trimethyl carbinol that contains salt of wormwood, at 80 DEG C～82 DEG C, reflux 1～3 hour, make dianhydrogalactitol, gained dianhydrogalactitol is dissolved in the trimethyl carbinol, add dianhydrogalactitol crystal seed, be cooled to-15 DEG C～0 DEG C, leave standstill 1～5 day, with anhydrous tertiary butanol washing, dry, obtain dianhydrogalactitol crystallization, lyophilize obtains dianhydrogalactitol lyophilized powder.
2. the method for preparing dianhydrogalactitol as claimed in claim 1, it is characterized in that: described silicon-dioxide is 5～10 object particles, its addition is 0.2～1.5% of xylose mother liquid dry biomass, and the addition of described gac is 5～8% of xylose mother liquid dry biomass.
3. the method for preparing dianhydrogalactitol as claimed in claim 1, it is characterized in that: in described step (2), the condition of shortening is: material liquid pH is 7.5～8.0, add radium niobium nickel catalyzator by 3～4% of dry biomass, temperature of reaction is 125～135 DEG C, pressure is 10～11MPa, and stirring velocity is 250～350r/min.
4. the method for preparing dianhydrogalactitol as claimed in claim 1, is characterized in that: the galactitol crystal seed in described step (3) is solid galactitol, and add-on is 1.5%～2.5% of feed liquid quality; Described growth stimulant is potassium acetate and dehydrated alcohol, and its add-on is respectively as 2.5%～4.5% of 0.015%～0.9% and material liquid volume of feed liquid quality.
5. the method for preparing dianhydrogalactitol as claimed in claim 1, it is characterized in that: in described step (3), the process of crystallization comprises: under stirring, be cooled to-15 DEG C～0 DEG C, leave standstill 5～10 days, centrifugal, hot ethanol dissolving for gained crystal, cooling recrystallization, absolute ethanol washing and dry, obtain crystallization galactitol.
6. the method for preparing dianhydrogalactitol as claimed in claim 1, it is characterized in that: the mitolactol kind crystalline substance adding in described step (5) is 1,6-mitolactol, described 1, in 6-mitolactol, contain 1,3-mitolactol massfraction is lower than 1%, and the brilliant add-on of described mitolactol kind is 1%～2% of feed liquid quality.
7. the method for preparing dianhydrogalactitol as claimed in claim 1, is characterized in that: the dianhydrogalactitol kind crystalline substance adding in described step (6) is 1,2,5,6-dianhydrogalactitol, described 1,2,5, in 6-dianhydrogalactitol, contain 1,2,4,5-dianhydrogalactitol is lower than 1%, and the brilliant add-on of described dianhydrogalactitol kind is 1%～2% of feed liquid quality.
8. the method for preparing dianhydrogalactitol as claimed in claim 1, is characterized in that: the amount that adds salt of wormwood in described step (6) in the trimethyl carbinol is to add the ratio of 10～20g salt of wormwood to add in every hundred milliliters of trimethyl carbinols.
9. the method for preparing dianhydrogalactitol as claimed in claim 2, it is characterized in that: the addition of described silica dioxide granule is 0.6～1.0% of xylose mother liquid dry biomass, the addition of described gac is 5.5～7.5% of xylose mother liquid dry biomass.
10. the method for preparing dianhydrogalactitol as claimed in claim 1, is characterized in that: described in step (1), preparation method's step of xylose mother liquid comprises the steps:
A, by one or more raw materials of selecting from corn cob, bagasse, Pith, cotton seed hulls and rice husk, be crushed to 1～2mm, add deionized water, be heated to 80～100 DEG C, insulated and stirred 2～5 hours, filter;
The solids of b, filtration adds the hydrochloric acid of 3～5 times of mass concentrations 3～5% of solids volume in solids, and under room temperature, the ultrasonication that is 100MHz through frequency 1～2 hour, is warming up to 100 DEG C of hydrolysis, refluxes 1～2 hour, and suction filtration obtains hydrolyzed solution;
C, said hydrolyzed liquid is heated to 75～80 DEG C, adding while stirring proportion is 0.9～1.05 calcium carbonate milk sap, in pH6～7.5 time, is incubated 1～2 hour, filter cleaner;
D, evaporation: reduction vaporization is concentrated into desired concn, obtain xylose mother liquid.
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